Movement Disorders
Movement disorders include a wide variety of disease states and physiological conditions. Non-limiting examples include various dyskinesias such as tremor, dystonia, chorea, athetosis, tic disorders, blepharospasm, as well as hemiballysmus, myoclonus, focal dystonias, such as writer's cramp and torticollis, restless leg syndrome and asterixis. These excessive or otherwise abnormal involuntary movements may vary significantly in rate, frequency, periodicity and progressionary character. Such movements may be seen in sometimes overlapping disorders such as Parkinson's disease; essential tremor, a.k.a. benign tremor or familial tremor; tic disorders, e.g. Tourette's syndrome; idiopathic dystonia (inducing writer's cramp), progressive supranuclear palsy and Wilson's disease. Movement disorders are different from seizure disorders in that movement disorders are often suppressible, they often subside or are absent during sleep and are distractable and not associated with the loss of consciousness.
Tremor is the most common of all movement disorders. Tremor is defined as an involuntary rhythmic, oscillatory movement about a joint produced by contractions of reciprocally innervated agonist/antagonist muscles, and is repetitive and regular in frequency. (Essential Tremor: A Practical Guide to Evaluation, Diagnosis, and Treatment, Clinician, Vol. 19 (No. 2), pgs. 1-15, 2001). It also ranks as one of the most debilitating symptoms in all of neurology. For example, the presence of even mild tremor in the upper extremities can make even the simplest of tasks impossible to perform. (Wasielewski P. G. et al., Pharmacologic Treatment of Tremor, Movement Disorders, Vol. 13, Supplement 3, 1998, pp 90-100). Essential tremor and tremor associated with Parkinson's disease are the most common types of tremor encountered in clinical practice. (Wasielewski P. G. et al., Pharmacologic Treatment of Tremor, Movement Disorders, Vol. 13, Supplement 3, 1998, pp 90- 100).
Essential tremor is the most common form of tremor and of all movement disorders and perhaps the most common primary neurological disorder. Estimates of the prevalence in the elderly population range from 1 to 22%, with 1-2% being a conservative number. (Findley L. J., Epidemiology and Genetics of Essential Tremor, Neurology, 2000, 54 (Suppl. 4), S8-S13). While often a minor problem and unassociated with other disease (hence the term “benign tremor or benign essential tremor”), it causes significant motor impairment for many individuals. In its classic form, it is a tremor involving the upper extremities and/or the head. Usually, it has a frequency of 5-8 Hz, is absent with rest, presents with a sustained posture and is not significantly exacerbated by movement. (Marsden C D. Origins of Normal and Pathological Tremor in Movement Disorders: Tremor. Eds. L. J. Findley and R. Capildeo, New York. Oxford University Press, 1984, pp. 37-84).
The cause and pathophysiology of essential tremor remain unknown. No pathologic substrate has been demonstrated in autopsy studies. Positron emission tomography (PET) studies of glucose metabolism and blood flow have demonstrated only general findings of increased activity in the brain stem (medulla), thalamus, cerebellum, striatum and sensorimotor cortex.
Parkinson's disease is a progressive disorder with a prevalence of 1-2% in people over the age of 50. It has a worldwide distribution and has no gender preference. Unlike essential tremor, untreated Parkinson's disease is life shortening. Symptoms of the disease include (1) shaking of the hands, arms, legs or feet while the patient is resting (the shaking may be more noticeable on one side of the body, and it may affect the hands more than the feet, the shaking often stops, however, as soon as the patient moves his limbs); (2) slowness of movement or a brief, temporary delay in movement; (3) difficulty in maintaining one's balance; (4) rigidity or stiffness of the patient's limbs; (5) facial masking (a still facial expression with fewer blinks of the eyes); (6) difficulty in speech; (7) difficulty swallowing; and (8) chorea and dystonic posturing, particularly as a side effect of treatment with dopaminergic agents. As the Parkinson's disease progresses, patients may be forced to work fewer hours and cut back on their activity level. Simple tasks become more of a challenge, and they may need some help from family and friends. Patients may find that using a wheelchair helps them move around more easily, and they may need help with daily activities.
Current Treatment of Movement Disorders
1. Treatment of Essential Tremor
Alcohol remains the most effective single agent for treatment of essential tremor. Estimates of patients responsive to alcohol range from 50-90%. (Koller, W. C., Hristove, A., Brin, M. Pharmacologic Treatment of Essential Tremor. Neurology 2000; 54 (Suppl 4), pp. S30-S38.) Its effect may be dramatic in some individuals. However, the half-life of alcohol is brief and the side effects are numerous.
Beta-adrenergic receptor blocking agents such as propranolol have also been widely used for over 30 years. However, even when beneficial, the clinical response is variable and incomplete. Moreover, beta-adrenergic blockers are probably of no benefit in 50% or more of patients.
The anticonvulsant primidone has been demonstrated to be effective in a significant subpopulation of patients. Comparative studies of primidone and beta-blocking agents variously report either therapeutic equivalency or slightly greater efficacy for primidone. Primidone, unlike beta-blocking drugs, will completely suppress tremor in some patients. (Findley, L. J., Cleeves, L., Caletti, S. Primidone in Essential Tremor of the Hands and Head: A Double Blind Controlled Clinical Study. J Neurol Neurosurg Psych, 1985, 48, pp. 911-915.) Primidone, however, produces a high incidence of side effects. Furthermore, primidone has little or no effect on head tremor, even in patients with a positive response of the limbs. Primidone is converted into two active metabolites, phenobarbital and phenylethylmalonamide (PEMA). PEMA has been found to have no anti-tremor effect.
Phenobarbital has some anti-tremor effect, but not as prominent as primidone or beta-blocking agents, particularly when the patients are assessed in terms of functional improvement. (Findley, L. J. The Pharmacology of Essential Tremor in Movement Disorders 2nd Edition. Morsden, C. D., Fahn S, Longdong : Butterworths, 1987. As detailed below, phenobarbital has sedative effects and can suppress respiration.
There have been brief reports of newer anticonvulsant drugs, particularly gabapentin, providing a benefit in treatment of essential tremor. (See Gironell, A., Kulisevsky, J., Lopez-Villegas, D., Hernandez, G., Pascual-Sedano, B., A Randomized Placebo-Controlled Comparative Trial of Gabapentin and Propanolol in Essential Tremor. Arch. Neurol., 1999, 56, pp. 475-480.) None of these other agents, however, have gained wide use for this indication, presumably because of their neurological side effects and/or limited efficacy. Methazolamide, a carbonic anhydrase inhibitor, has been reported to be of some benefit. (Meunter, M. D., Daube, J. R., Caviness, J. N., Miller, P. M. Treatment of Essential Tremor with Methazolamide. Mayo Clinic Proc, 1991, 66, pp. 991-997.) However, primidone and propranolol are the only two prescription drugs with proven efficacy in general clinical practice. Louis, E. D., N. Eng. J. Med., 345, (12), 2001, pp.887-891.
U.S. Pat. No. 6,281,207 to Richter et al. discloses methods of combating movement disorders such as tremor by administering mirtazapine.
Surgical treatment of severe disabling essential tremor is sometimes useful. This has most commonly involved thalamotomy (lesioning of the thalamus) and, more recently, the use of surgically implanted electrodes. These procedures however have considerable potential morbidity.
Therefore, there exists a need for a method of treating essential tremor and other movement disorders having minimal adverse side effects, high tolerance, and significant effectiveness.
2. Treatment of Parkinson's Disease
The most widely recognized drug for the treatment of Parkinson's disease is levodopa, a medication that is converted into dopamine when it crosses into the brain. Levodopa reduces the symptoms of this disease because dopamine is the chemical that is necessary for human muscles to function normally. It is called a replacement drug because it replaces dopamine. For most patients with Parkinson's disease, levodopa provides significant improvement in many symptoms, including tremor. However, the therapeutic benefits of this drug usually last for only a limited period of time. After about 3 to 5 years of treatment, levodopa becomes less effective in reducing symptoms in most patients. At times the patient can move around easily or with slight tremor and rigidity, and at other times the patient has difficulty with movement, as if the medicine is “wearing off.” For this reason, doctors try to keep the dose of levodopa as low as possible or may not begin treatment with levodopa until the symptoms can no longer be managed by other means. (Lang, A. E. et al., N. Eng. J. Med., 339 (16), 1998, pp. 1130-1143).
The side effects of levodopa include nausea, vomiting, loss of appetite, rapid heart rate, and lowered blood pressure when a person stands from a sitting position. To reduce these side effects, levodopa is often prescribed in combination with carbidopa, and this drug combination is marketed under the trademark Sinemet™ (Bristol-Myers Squibb). The carbidopa in Sinemet™ prevents levodopa from being metabolized in the stomach and liver, so more of the levodopa can get to the brain, which permits administration of a smaller dose of levodopa or alternatively increases the effectiveness of a given administered dose of levodopa. Even though carbidopa helps to reduce the side effects of levodopa, many patients who take Sinemet™ may still experience nausea, vomiting, and loss of appetite when they begin taking it or after their dosage is increased. Other side effects of carbidopa/levodopa combination medications include dry mouth, daytime sleepiness, nervousness, vivid dreams, insomnia, and a form of motor fluctuation called dyskinesia, characterized by involuntary writhing movements. Sometimes dyskinesia results when the dosage of the medication is too high.
Another group of medications for Parkinson's Disease is dopamine agonists. Dopamine agonists are drugs that stimulate the parts of the human brain that normally respond to dopamine. In effect, the brain “thinks” it is receiving dopamine, so these drugs help satisfy the brain's need for dopamine. The most commonly used dopamine agonists in the United States include Parlodel™ (bromocriptine, Novartis), Permax™ (pergolide mesylate, Amarin), MIRAPEX™ (pramipexole hydrochloride, Pharmacia & Upjohn) and Requip™ (ropinirole, GlaxoSmithKline). Parlodel™ and Permax™ are synthetic derivatives of a chemical called “ergot”. The side effects are similar to those of levodopa: nausea, vomiting, confusion, hallucinations, lightheadedness and fainting. A rare side effect known as fibrosis (membrane lining of body organs can become thickened or scarred) has also been reported. MIRAPEX™ has been shown to be effective in treating the symptoms of early disease without levodopa. During the advanced stages, taking MIRAPEX™ in combination with levodopa may reduce the dose of levodopa that is needed. The use of MIRAPEX™ can cause drowsiness and the possibility of suddenly falling asleep during daily activities, which could result in an accident while driving. The most common side effects of MIRAPEX™ are nausea, sleeplessness, constipation, involuntary movement, sleepiness, dizziness upon standing, and hallucinations.
Another group of medications for Parkinson's Disease is catechol-O-methyltransferase (COMT) inhibitors (e.g., Tasmarm™ (tolcapone, Roche Laboratories) and Comtan™ (entacapone, Novartis)). COMT is one of two enzymes that break down levodopa before the brain converts it into dopamine. When the COMT enzyme is blocked by the COMT inhibitors, dopamine stays in the brain for a longer period of time. COMT inhibitors are usually taken with levodopa. The most common side effects reported by patients who have taken COMT inhibitors include unusually vivid dreams or visual hallucinations, nausea, difficulty in sleeping, daytime drowsiness, headache, and excessive involuntary movements. In addition, in 1998 the U.S. Food and Drug Administration reported that Tasmar™ can cause liver damage, so now doctors are advised to monitor their patients who are taking this drug on a regular basis to make sure their liver is functioning normally.
Anticholinergics have also been used in the treatment of Parkinson's disease. Before doctors begin treating Parkinson's disease patients with levodopa, they may prescribe anticholinergic drugs such as Artane™ to relieve symptoms. When the brain cannot get enough dopamine, it produces increased quantities of a chemical called acetylcholine, and too much acetylcholine causes tremor and rigidity in patients. Anticholinergic drugs block the effect of acetylcholine, so they are effective in reducing tremor and rigidity in patients. Anticholinergics are not usually prescribed for long periods of time because of the side effects they cause in patients, which include dry mouth, blurred vision, constipation, difficulty in urinating, confusion, and hallucinations.
Dopamine is broken down in the brain by an enzyme called monoamine oxidase (MAO). Hence, selegiline and other MAO inhibitors help the brain make the most of the dopamine that is still being produced and/or dopamine that is being supplied to the brain by other drugs. When a Parkinson's disease patient takes an MAO inhibitor, it slows down the progress of this enzyme, which increases the amount of dopamine that is available to the brain. The side effects of selegiline include heartburn, loss of appetite, nausea, dry mouth, dizziness, constipation, and insomnia.
Anti-viral agents such as Symmetrel™ (amantadine, Endo Labs) provide mild relief of Parkinson's symptoms in newly-diagnosed patients. It has been used to treat this disease for many years, but even today, medical researchers and doctors aren't really sure how it works in the human brain. Unfortunately, it tends to cause insomnia and daytime fatigue, and other side effects that have been reported include red or purple skin blotches (often on the patient's legs), swelling of the feet, anxiety, dizziness, difficulty in urinating, and hallucinations. (Lang, A. E. et al., N. Eng. J. Med., 339 (16), 1998, pp. 1130-1143).
U.S. Pat. No. 6,281,207 to Richter et al. discloses methods of combating movement disorder such as Parkinson's disease by administering mirtazapine.
Surgery can dramatically reduce symptoms for some patients in the advanced stages of Parkinson's disease. Doctors may suggest surgery as an option for such patients because they have been taking combinations of drugs over a long period of time, and those drugs have become less and less effective. A pallidectomy or pallidotomy is a surgical procedure in which a lesion is created in a specific area of the brain (globus pallidus) to help restore the balance required for normal motion. The majority of patients who have had this surgery have gained immediate, significant improvements in their ability to function, and those benefits have lasted for at least a year. Deep brain stimulation (DBS) has also been used by physicians as a preferred alternative to a pallidotomy. Although these surgical approaches have produced some desirable results, the long-term effects of such surgeries for Parkinson's patients are not yet known. Therefore, doctors generally reserve these as last resort treatments for their patients. (Lang, A. E. et al., N. Eng. J. Med, 339 (16), 1998, pp. 1130-1143).
In view of the above, there exists a need for a method of treating movement disorders that are either symptoms of or associated with Parkinson's disease or not using an active agent having minimal adverse side effects, high tolerance, and significant effectiveness.
Barbituric Acid Derivatives
1. Sedating Barbituric Acid Derivatives
Barbiturates (or barbituric acid derivatives) have been developed and have been used as the primary drugs for the treatment of insomnia for many years. Barbiturates depress both the respiratory drive and the mechanisms responsible for the rhythmic character of respiration. (Goodman & Gilman's, The Pharmacological Basis of Therapeutics, Chapter 17, 9th Edition, McGraw-Hill). They have been implicated in thousands of deaths due to accidental (or deliberate) ingestion (resulting in homicide, suicide or accidental death) since they are associated with serious, often fatal, central nervous system (CNS) depressive effects following acute overdosage. Barbiturates have been chronically abused by a substantial portion of the population. When coadministered with other drugs, barbituatates may interact with them with a potentially lethal outcome. Currently or previously clinically employed barbiturates include amobarbital, barbital, butabarbital, and hexobarbital, mephobarbital, pentobarbital, phenobarbital, secobarbital, thiamylal, and thiopental. Barbiturates with a short to intermediate duration of action (e.g., amobarbital, butabarbital, pentobarbital, secobarbital, and vibarbital) are used as sedative-hypnotics. Phenobarbital is used as an anticonvulsant for the treatment of seizure disorders. Ultrashort-acting barbiturates (e.g., thiamylal and thiopental) can be used as anesthetics. (Craig, C. R. and Stitzel R. E., Modern Pharmacology, Chapter IV, 2nd Edition, 1986, Little, Brown and Company, Boston/Toronto).
As mentioned above, sedative barbiturates such as phenobarbital have been found to have some anti-tremor effect. However, its effectiveness is severely limited by its strong side effects.
2. Non-Sedating Barbituric Acid Derivatives
U.S. Pat. No. 4,628,056 (“the '056 Patent”) to Levitt et al. discloses novel oxopyrimidine derivatives of the general formula

wherein R1 and R2 may be the same or different and are each hydrogen or lower alkyl optionally substituted by lower alkoxy, and R3 and R4 may be the same or different and are each phenyl optionally substituted by lower alkyl or halogen, provided that when R1 and R2 are both hydrogen, R3 and R4 are each substituted phenyl. The '056 Patent discloses that these compounds are useful as anticonvulsants, and antianxiety agents and as muscle relaxants. According to the '056 Patent, animals given such compounds continue to behave normally and do not show any observable effects on locomotion, escape behavior or feeding behavior. The '056 Patent further elaborates that the compounds disclosed therein are useful in treating mammals for strain and stress conditions and nervous dysfunctions such as convulsions, seizure, muscle stiffness, nervous strain and anxiety. The '056 Patent does not mention or suggest that such compounds can be used to treat any movement disorders.
U.S. Pat. No. 6,093,820 (“the '820 Patent”) to Gutman et al. discloses that alkoxyalkylated ureide compounds such as N-methoxymethyl ethosuximide, N-methoxymethyl glutethimide, and N-methoxymethyl-5,5-diphenylbarbituric acid are also useful in treating convulsions, seizures, muscle stiffness, or anxiety. Again, the '820 Patent doses not mention or suggest that any of these compounds can be used to treat any movement disorders.